1. Field of the Invention
The invention relates to the use of peripherally selective kappa opioid receptor agonists to elevate serum levels of prolactin for the benefit of a mammal in need of such elevation.
2. Background
Prolactin is a 198 amino acid polypeptide synthesized in pituitary lactotrophs, which constitute about 20 percent of adenohypophysial cells (for review, see Harrison's Principles of Internal Medicine, 16th Ed., p. 2084; also Freeman M E et al. Prolactin: Structure, function, and regulation of secretion. Physiol. Rev. 80: 1523 1631, 2000). Prolactin is also referred to in the art as Galactin, Lactogen, Lactoropin, LMTH, LTH, Luteomammotrophic Hormone, Luteotrophic Hormone, Luteotropin, and Mammotrophin, although these names are now obsolete. The best studied effects of prolactin are on the mammary gland, and include growth and development of the mammary gland (mammogenesis), synthesis of milk (lactogenesis), and maintenance of milk secretion (galactopoiesis). The endocrine control of lactation involves multiple complex physiological mechanisms since mammogenesis, lactogenesis, galactopoiesis, and galactokinesis are all essential for proper lactation. Prolactin is the key hormone of lactation and is believed to be the single most important galactopoietic hormone. Oxytocin, serotonin, opioid peptides, histamine, substance P, and other physiological substances modulate prolactin release by means of an autocrine/paracrine mechanism at the level of the hypothalamus, whereas estrogen and progesterone hormones can act at the hypothalamic and adenohypophysial levels. Human placental lactogen and growth factors play an essential role in successful lactation during pregnancy, with oxytocin functioning as a key galactokinetic hormone.
Normal adult serum prolactin levels are about 10-25 ng/ml in women and 10-20 ng/ml in men. Prolactin is secreted in an episodic manner with a distinct 24 hour pattern. Circulating prolactin levels are lowest at midday, and a modest increase occurs during the afternoon. Prolactin levels increase shortly after onset of sleep, peaking in the early morning. Serum prolactin levels rise substantially during pregnancy (150-200 ng/ml) and decline rapidly within two weeks of parturition. Breastfeeding will normally cause prolactin levels to remain elevated, due to suckling induced activation of neural reflexes that that induce prolactin release. However, inadequate activation of prolactin release will interfere with breastfeeding, with a variety of potentially deleterious psychological and physiological consequences, e.g., a failure of mother infant bonding and a failure to transmit maternal protective antibodies to the infant (American Academy of Pediatrics, Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 115: 496-506, 2005). According to the American Academy of Pediatrics, in this most current version of their guidance on breastfeeding, “Extensive research using improved epidemiologic methods and modern laboratory techniques documents diverse and compelling advantages for infants, mothers, families, and society from breastfeeding and use of human milk for infant feeding. These advantages include health, nutritional, immunologic, developmental, psychologic, social, economic, and environmental benefits.” Because of the well documented benefits of breastfeeding, insufficient lactation is now viewed as an important medical problem.
There are numerous risk factors for insufficient lactation, including:                (i) restarting lactation after termination, e.g., to care for a sick infant (Thompson N Relactation in a newborn intensive care setting. J. Hum. Lact. 12: 233-235, 1996).        (ii) physical abnormality of the breast (Neifert M R et al. Lactation failure due to insufficient glandular development of the breast. Pediatrics 76:823-828, 1985).        (iii) absence of breast enlargement during pregnancy (Moon J et al. Breast engorgement: contributing variables and variables amenable to nursing intervention. J. Obstet. Gynecol. Neonatal Nurs. 18: 309-315, 1989).        (iv) history of breast surgery (Widdice L The effects of breast reduction and breast augmentation surgery on lactation: An annotated bibliography. J. Hum. Lact. 9:161-163, 1993).        (v) first time delivery of infant (Dewey K G et al. Risk factors for suboptimal infant breastfeeding behavior, delayed onset of lactation, and excess neonatal weight loss. Pediatrics 112:607-619, 2003).        (vi) premature delivery of infant (Ehrenkranz R A et al. Metoclopramide effect on faltering milk production by mothers of premature infants. Pediatrics; 78:614-20, 1986; Feher S D K et al. Increasing breast milk production for premature infants with a relaxation/imagery audiotape. Pediatrics 83:57-60, 1989).        (vii) delivery of more than one infant (Leonard, L. Breastfeeding higher order multiples: Enhancing support during the postpartum hospitalization period. J. Hum. Lact. 18:386-392, 2002).        (viii) adoption of infant (Cheales Siebenaler, N. Induced lactation in an adoptive mother. J. Hum. Lact. 15:41-43, 1999).        (ix) retention of placental fragments (Neifert, M R et al. Failure of lactogenesis associated with placental retention. Am. J. Obstet. Gynecol. 140:477-478, 1981).        (x) use of hormonal birth control (Tankeyoon M et al. Effects of hormonal contraceptives on milk volume and infant growth. WHO Special Programme of Research, Development and Research Training in Human Reproduction Task force on oral contraceptives. Contraception 30:505-22, 1984).        (xi) use of certain OTC decongestants (Aljazaf K et al. Pseudoephedrine: effects on milk production in women and estimation of infant exposure via breastmilk. Br. J. Clin. Pharmacol. 56:18-24, 2003).        (xii) cigarette smoking (Andersen A N et al: Suppressed prolactin but normal neurophysin levels in cigarette smoking breast feeding women. Clin. Endocrinol. (Oxf.) 17:363-8, 1982).        (xiii) prepregnant overweight and obesity (Hilson J A et al. High prepregnant body mass index is associated with poor lactation outcomes among white, rural women independent of psychosocial and demographic correlates. J. Hum. Lact. 20:18-29, 2004; Rasmussen K M et al. Prepregnant overweight and obesity diminish the prolactin response to suckling in the first week postpartum. Pediatrics 113:465-71, 2004).        (xiv) Cesarean delivery (Chapman D J et al. Identification of risk factors for delayed onset of lactation. J. Am. Diet. Assoc. 99:450-454, 1999).        (xv) insulin dependent maternal diabetes (Neubauer, S H et al. Delayed lactogenesis in women with insulin dependent diabetes mellitus. Am. J. Clin. Nutr. 58:54-60, 1993).        (xvi) medications to treat labor pain (Riordan J et al. The effect of labor pain relief medication on neonatal suckling and breastfeeding duration. J. Hum. Lact. 16:7-12, 2000; Ransjo Arvidson A B et al. Maternal analgesia during labor disturbs newborn behavior: effects on breastfeeding, temperature, and crying. Birth 28:5-12; 2001).        (xvii) stress (Chen D C et al. Stress during labor and delivery and early lactation performance. Am. J. Clin. Nutr. 68:335-344, 1998; Dewey K. Maternal and fetal stress are associated with impaired lactogenesis in humans. J. Nutr. 131:3012 S-3015S, 2001).        
Signs of insufficient lactation in a human infant include: (1) insufficient weight gain in an infant who is receiving food only by breast feeding, even if the infant appears content; (2) infant latching on poorly; (3) infant sucking inconsistently; (4) inconsistency of let down reflex, and (5) evidence of hunger, indicated by crying soon after feedings.
Lactation failure in humans is a common clinical event with serious emotional sequelae. It has been considered to be a significant problem in 5 to 10% of all lactations. In many instances this leads to premature initiation of supplements or total weaning. This is considered to be an inferior child rearing practice and may be harmful to certain infants with an increased risk of gastritis and other disorders. Many affected women are severely emotionally distressed by their perceived inadequacy, thus affecting the parent child bond. Failure to thrive in infants is not uncommon if the mother refuses to supplement.
There has therefore been a long need for a medicament that can promote human lactation, e.g., when there is insufficient lactation after the birth of the child. For animal breeders, the inability of their livestock, e.g., mares, to produce and secrete milk after giving birth can be a significant problem. Should the breeding animals not lactate properly, the offspring must then be bottle fed, which is time consuming, labor intensive, and costly; thus, there is a need for a medicament to safely and effectively promote breeding animal lactation. For commercial milk producing animals like cows and goats, there is an economic need to safely and effectively increase their milk production above a normal level.
A number of causes of reductions in prolactin levels that are associated with insufficient lactation were noted above. Certain of these causes are also associated with reduced prolactin levels in non-lactating subjects, e.g., cigarette smoking (Fuxe K et al. Neuroendocrine actions of nicotine and of exposure to cigarette smoke: medical implications. Psychoneuroendocrinology 14: 1.9-41, 1989). Other causes of low prolactin levels (hypoprolactinemia) include the use of various therapeutic agents, such as L deprenyl for the treatment of migraine (Fanciullacci M et al. Dopamine involvement in the migraine attack. Funct Neurol. 15 Suppl 3:171-81, 2000). Hypoprolactinemia of unknown origin has also been associated with poor sperm motility in adult men (Gonzales G F et al. Hypoprolactinemia as related to seminal quality and serum testosterone. Arch. Androl. 23:259-65, 1989), a finding that is supported by the observation that pharmacological suppression of prolactin release for several weeks in young men decreased subsequent hCG stimulated testosterone secretion (Oseko F et al. Effects of chronic bromocriptine induced hypoprolactinemia on plasma testosterone responses to human chorionic gonadotropin stimulation in normal men. Fertil. Steril. 55:355-357, 1991). Hypoprolactinemia could also contribute to age related changes in physiological functions. Serum prolactin concentrations tend to fall with age, e.g. in older men and estrogen unreplaced postmenopausal women (Maddox P et al. Bioactive and immunoactive prolactin levels after TRH stimulation in the sera of normal women. Horm. Metab. Res. 24:181-184, 1992; Maddox P et al. Basal prolactin and total lactogenic hormone levels by microbioassay and immunoassay in normal human sera. Acta Endocrinol. (Copenh.) 125:621-627, 1991). Remarkably, a comparable quantitative reduction in prolactin secretion occurs in critically ill individuals (Van den Berghe G et al. Thyrotropin and prolactin release in prolonged critical illness—dynamics of spontaneous secretion and effects of growth hormone secretagogues. Clin. Endocrinol. (Oxf.) 47:599-612, 1998) as well as in patients with poorly controlled type I diabetes mellitus (Iranmanesh A et al. Attenuated pulsatile release of prolactin in men with insulin dependent diabetes mellitus. J. Clin. Endocrinol Metab. 71:73-78, 1990). Hypoprolactinemia is also reported to be a risk factor for prolonged lymphopenia and apoptosis associated depletion of lymphoid organs in nosocomial sepsis related death in critically ill children (Felmet K A et al. Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J. Immunol. 174:3765-72, 2005). The findings reviewed above indicate that prolactin deficiency may contribute to impaired testosterone dependent functioning and age related changes as well as vulnerability to illness.
In addition to the apparent roles of prolactin discussed above, there is evidence that prolactin is important for maintenance of rapid eye movement sleep (REM sleep), which is essential for normal brain function. After observing that pregnancy associated sleep enhancement is correlated with the daily surges of prolactin, investigators found that administration of prolactin to female rats significantly increased REM sleep (Zhang S Q et al. Effects of prolactin on sleep in cyclic rats. Psychiatry Clin. Neurosci. 53:101-3, 1999). Consistent with these findings, induction of experimental hypoprolactinemia in male rats was found to decrease REM sleep (Obál Jr F et al. Antiserum to prolactin decreases rapid eye movement sleep (REM sleep) in the male rat. Physiol. Behav. 52:1063-1068, 1992). These findings indicate that subjects experiencing insufficient REM sleep could benefit from elevations in prolactin.
Based on the findings reviewed above, there is a need for a medicament that can safely and effectively elevate prolactin level in a variety of subjects with functional hypoprolactinemia, particularly including females experiencing insufficient lactation, but also males experiencing insufficient testosterone related functions, and both females and males who are suffering from the effects of severe illness, including type I diabetes, or who are suffering the effects of insufficient REM sleep, e.g., due to insomnia.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.